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2011 Call for projects in the field of viral safety for biological products
   
  » Outcome

Selected projects 2009

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Risk assessment of insoluble PrP from normal human brains

Wen-Quan Zou - Case Western Reserve University,Cleveland - USA

Prion diseases are a group of incurable, transmissible spongiform encephalopathies affecting both animals and humans. The critical molecular event in the pathogenesis of prion diseases, involving the conversion of a cellular prion protein (PrPC) into its pathological and infectious forms (PrPSc, or prions), remains poorly understood (Prusiner, 1998).

We have recently provided the first experimental evidence that small amounts of detergent-insoluble PrP aggregates and PK-resistant PrP species (iPrP) are present in uninfected human and animal brains (Yuan et al., 2006).
The long-term objective of this project is to investigate the in vivo pathways of conversion of brain PrPC into PrPSc. We hypothesize that iPrP, identified in uninfected brains, actually is identical to PrP*.

Three Specific Aims will be addressed in this study: 1) to determine the differences in physicochemical features of PrP aggregates, and to dissect PrP aggregate-containing complexes isolated by gene 5 protein (specific abnormal PrP-binding reagent), from normal and prion-infected human brains by using two-dimensional gel electrophoresis and mass spectrometry; 2) to examine whether iPrP is more prone to form PrPSc than PrPC in vitro by using protein misfolding cyclic amplification; and 3) to determine whether iPrP prepared by enrichment is infectious and/ or neurotoxic, by using transmission study in primates. The proposed study will improve our understanding of PrPSc formation in the spontaneous prion diseases, and will facilitate the development of early diagnostic and therapeutic strategies.

 

 
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